High-Throughput Screening of Meningiomas Identifies Proteasome Inhibition as a Potential Treatment Avenue

Objective: Meningiomas are common brain neoplasms that account for 33.8% of all primary brain tumors. Approximately 20 to 35% of meningiomas are considered higher grade by the World Health Organization which have poor clinical outcomes. Lower grade meningiomas also have been shown to cause long-term neurological deficits and reduced overall survival. Despite the high incidence of these tumors, meningiomas lack an FDA-approved compound for treatment. To address the lack of a pharmacological agent available for meningiomas, we maintain an on-going high-throughput screening study. Previously, we reported on both an epigenetic and FDA-approved screen in 30 meningiomas that identified histone-deacetylase (HDAC) inhibition as a potential therapy for these tumors. However, continued screening has shed light on additional potential therapies. Here, we present an expanded cohort of 44 meningiomas and identify carfilzomib, an irreversible 20 S and 26 S proteasome inhibitor, as the most effective compound in our screen.

Methods: In this study, we cultured 39 meningiomas from our neural tissue bank and five meningioma cell lines. We screened our cohort against a library of 123 FDA-approved compounds to identify potential candidate drugs. Cell viability was assessed with an MTS assay 72 hours after a 1 µM single-dose compound treatment.

Results: While each meningioma screened exhibited a unique sensitivity profile, we identify carfilzomib, romidepsin, and panobinostat as broadly effective compounds against most tumors in our cohort. Distinctive from our previous findings implicating HDAC inhibition, carfilzomib was identified as the most broadly effective compound, reducing the average cell viability of the cohort, regardless of tumor grade, patient gender, history of prior treatment, or recurrence status. Carfilzomib was the most effective compound in 24 of 44 tumor samples and significantly reduced cell viability in 41 of 44 tumors in our cohort.

Conclusion: We present an analysis of an expanded cohort of tumors screened against a library of FDA-approved compounds. While our current findings still support HDAC inhibition as a potential avenue for meningioma treatment, our data now suggest an important role for the proteasome in meningioma tumor biology. These results indicate that targeting the 20 S and 26 S proteasome subunits may show potential for novel therapies for meningiomas. Further validation studies are needed.

 

MissingLinkText

Die Autoren geben an, dass kein Interessenkonflikt besteht.

Publikationsverlauf

Artikel online veröffentlicht:
15. Februar 2022